¹University of Illinois at Chicago, Chicago, IL, USA

Abstract

Although human hepatocytes usually provide an accurate estimate of drug metabolism in vivo, oral CLZ appears to induce CYP3A4 in vitro and inhibit CYP3A4 in vivo. This discrepancy indicates that predicting the effect of a drug on CYP activity in vivo from hepatocytes may be limited. Therefore, we investigated the effects of oral CLZ on CYP3A4 activity using midazolam (MDZ) as a specific probe. Ten healthy volunteers randomly received oral CLZ 10mg 3 times daily x 5 days or no treatment (C) before their study visit. The study included 2 inpatient (oral MDZ 2mg) and 2 outpatient visits (IV MDZ 0.025 mg/kg) with the visits separated by 2 weeks. Blood samples were drawn at the following times: 0, 0.5, 1, 2, 4, 5, 6, 12 and 24 h after oral MDZ and 0, 0.25, 0.5, 1, 2, 4, 5, 6 h after IV MDZ. The plasma concentrations for MDZ were quantified using high performance liquid chromatography and were fitted to a non-compartmental model. The maximal plasma concentration (CLZ 18|[plusmn]|7.8 vs. C 12|[plusmn]|4.7 ng/ml; p<0.025) and area under the curve (CLZ 55|[plusmn]|12 vs. C 42|[plusmn]|14 ng|[ast]|h/ml; p=0.040) for oral MDZ increased after receiving CLZ. In contrast, CLZ did not affect the pharmacokinetic parameters for IV MDZ. The plasma concentrations of CLZ and 1-hydroxyMDZ will be determined, as well. In summary, CLZ increases the systemic absorption of orally administered CYP3A4 substrates, but does not affect the systemic clearance of IV administered CYP3A4 substrates.